AB1444 ASSOCIATION BETWEEN THIOPURINE S-METHYLTRANSFERASE POLYMORPHISMS AND HEPATOTOXICITY IN AZATHIOPRINE-TREATED PATIENTS WITH AUTOIMMUNE DISEASES
Authors: S. Heh-Shiang, W. T. Hung, W. Chia-Yi, W. N. Huang, Y. H. Chen, Y. M. Chen
Journal: Annals of the Rheumatic Diseases (2022)

Background Azathioprine(AZA) is widely used in patients with autoimmun diseases. Thiopurine methyltransferase (TPMT) is the rate-limiting enzyme in AZA metabolization. Although several studies have investigated the association between TPMT polymorphisms and AZA-induced bone marrow suppression, the relationship of TPMT genotypes and hepatoxicity in patients taking AZA remained unclear. Objectives This study aimed to investigate the correlation between TPMT polymorphisms and adverse reactions of AZA. Methods This retrospective case-control study enrolled patients with prior exposure to AZA at the Taichung Veterans General Hospital (TCVGH) using data extracted from the Taiwan Precision Medicine Initiative (TPMI) cohort. Drug-prescription profile, comorbidities, the occurence of leukopenia and hepatotoxicity following AZA treatment were extracted from hospital health records. Genetic variatns affecting TPMT activity were determined using SNP array. Participants were categorized into normal metabolizer (NM) and non-normal metabolizer (Non-NM) groups accordingly. Results From the 43,035 patients in the TCVGH-TPMI cohort, we identified 2,128 azathioprine users; 2.6% (57 out of 2,128) were classified as TPMT Non-NM group. After matching by age and sex, we included 50 TPMT Non-NM, including 1 poor metabolizers (PMs), 49 intermediate metabolizers (IMs), and 1,000 NM patients for further analysis. The Non-NM genotype was associated with hepatotoxicity compared with NM genotype (HR: 3.85, 95% CI: 1.83–8.10) after adjustment for gender, AZA dosage, and comorbidities(Table 1). In the Non-NM group, the 3-year cumulative incidence of hepatotoxicity was 6.6% for one year, 16.9% for two and three years, respectively, which was significantly higher than the NM group ( p =0.003)(Figure 1). Table 1. Cox regression analysis of risk factors for hepatotoxicity following AZA treatment Hepatotoxicity* p value HR 95% CI Age 0.99 0.98 1.01 0.60 Male gender 1.77 1.07 2.91 0.03 TPMT non-NM genotype 3.85 1.83 8.10 0.0004 AZA dose (mg ) 1.00 1.00 1.01 0.31 Medication MTX 1.62 1.03 2.57 0.04 Comorbidity Hepatitis B carrier 1.18 0.40 3.48 0.76 By Cox regression model with adjustment of all listed variables. *Development of GPT ≥ 150 U/L after AZA treatment; GPT, glutamic pyruvic Transaminase; TPMT, thiopurine S-methyltransferase; NM, normal metabolizer; AZA, azathioprine; MTX, Methotrexate; CI: confidence interval Figure 1. Cumulative incidence of hepatotoxicity Conclusion TPMT Non-NM genotype were associated with the developement of hepatotoxicity following AZA therapy. Prospective studies are needed to varify our results. References [1]Liu, Y.P., et al., Association between thiopurine S-methyltransferase polymorphisms and thiopurine-induced adverse drug reactions in patients with inflammatory bowel disease: a meta-analysis. PLoS One, 2015. 10 (3): p. e0121745. Disclosure of Interests None declared